Incontinence associated with sexual activity encompasses several forms, including orgasm-associated incontinence and climacturia, and can involve incontinence at different points along the sexual spectrum, for example, at penetration, during intercourse, or at climax. The condition can be associated with disorders including overactive bladder (OAB) and neurogenic detrusor overactivity (NDO), and has received increasing attention in the medical literature. Additionally, it can significantly impact sexual satisfaction among both sufferers (both men and women) and their partners. Some male sufferers develop incontinence associated with sexual activity following prostate surgery such as radical prostatectomy (RP; removal of the prostate) or brachytherapy.
Prostate cancer is the second most commonly diagnosed cancer in males in the United States, accounting for approximately 33% of new cancer cases, and is the third leading cause of cancer-related death in men. Several surgery-related complications are associated with RP, including urinary incontinence and sexual dysfunction. The nature and degree of sexual dysfunction can vary widely following RP, including erectile dysfunction, loss of libido, orgasm alterations (anorgasmia, decreased orgasmic intensity, dysorgasmia and orgasm-associated incontinence) and decreased sexual satisfaction. Abouassaly and coworkers (Abouassaly R, Lane B. Lakin M, Klein E, Gill I. Ejaculatory incontinence after radical prostatectomy: a review of 26 cases. Program and abstracts of the Sexual Medicine Society of North America Fall Meeting; Nov. 17-20, 2005; New York, N.Y. Abstract 1) reported their findings with men who had climacturia after having undergone radical prostatectomy. Of an estimated 220 patients evaluated, 26 men experienced urine leak almost exclusively at the time of orgasm. The average age of the patients was 62 years. Patients experienced anywhere from 3 to 120 mL of urine leak (by patient self-report) at the time of orgasm. The authors felt that the occurrence of ejaculatory incontinence is high enough to be considered as part of the routine post-prostatectomy evaluation. In a 2006 study of 42 men, two years following RP, 68% reported experiencing climacturia. Forty-eight percent felt that it was a significant bother to them. In a 2007 study of 475 patients, 20% reported incontinence associated with sexual activity following radical pelvic surgery. Men were more likely to experience it in the first twelve months following surgery than later. Common methods of dealing with incontinence associated with sexual activity include emptying the bladder before sex and wearing a condom during sex. Thus, improved treatment methods are sought.
Men can also display a form of stress incontinence after RP wherein incontinence can occur during intercourse and continue through climax.
In women, incontinence associated with sexual activity may be associated with detrusor overactivity linked to overactive bladder (OAB), or to neurogenic detrusor overactivity (NDO)—one study has found that orgasm can produce an uninhibited detrusor contraction. It has also been associated with female ejaculation in the absence of OAB (Cartwright, 2007) or other urodynamic abnormality. Additionally, some researchers speculate that incontinence associated with sexual activity can be linked with stress or sphincter incontinence. This incontinence can, as in the case with males, occur at any point from before penetration to after climax.
Coital Incontinence (CI) is urinary leakage that occurs during either penetration or orgasm and can occur with a sexual partner or with masturbation. It has been reported to occur in 10% to 24% of sexually active women with pelvic floor disorders, yet CI may still be an underreported problem since sexual or urinary dysfunction may not be often or readily discussed due to patient or physician embarrassment. Unfortunately, CI can have a disturbing impact on Quality of Life (QoL) and sexuality. Women rarely refer to it spontaneously, with only 3% of women self-reporting sexual disorders including CI; even with direct questioning, only 20% will admit to it. The impact on QoL from CI is significant. Sexually active women with CI reported a worse QoL than those without it.
Coital incontinence is divided into 2 subtypes based on when urinary leakage occurs: incontinence with penetration and incontinence with orgasm. Each has different pathophysiologic causes. In the original series of 79 patients with CI, two-thirds experienced CI with penetration, while one-third did so with orgasm. After uro-dynamic testing, CI with penetration was strongly correlated to stress urinary incontinence, while CI from orgasm was strongly correlated with detrusor overactivity. A larger, more recent series of 132 women confirms the findings that the majority of women, 63%, experience CI from penetration, while 37% do so from orgasm.
Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of botulinum toxin type A (available from Allergan, Inc., of Irvine, Calif. under the tradename BOTOX®) is an LD50 in mice. One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each. Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G, each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. The botulinum toxins apparently bind with high affinity to cholinergic motor neurons, are translocated into the neuron and block the release of acetylcholine.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. Botulinum toxin type A has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus, hemifacial spasm, cervical dystonia, and migraine headaches. Botulinum toxin type B has also been approved by the FDA for the treatment of cervical dystonia. Clinical effects of peripheral intramuscular botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of botulinum toxin type A averages about three months.
It has been reported that botulinum toxin type A has been used in clinical settings as follows:
about 75-125 U (U) of BOTOX® per intramuscular injection (multiple muscles) to treat cervical dystonia;
5-10 U of BOTOX® per intramuscular injection to treat glabellar lines (brow furrows) (5 U injected intramuscularly into the procerus muscle and 10 U injected intramuscularly into each corrugator supercilii muscle);
about 30-80 U of BOTOX® to treat constipation by intrasphincter injection of the puborectalis muscle;
about 1-5 U per muscle of intramuscularly injected BOTOX® to treat blepharospasm by injecting the lateral pre-tarsal orbicularis oculi muscle of the upper lid and the lateral pre-tarsal orbicularis oculi of the lower lid.
to treat strabismus, extraocular muscles have been injected intramuscularly with between about 1-5 U of BOTOX®, the amount injected varying based upon both the size of the muscle to be injected and the extent of muscle paralysis desired (i.e. the amount of diopter correction desired).
to treat upper limb spasticity following stroke by intramuscular injections of BOTOX® into five different upper limb flexor muscles, as follows:
(a) flexor digitorum profundus: 7.5 U to 30 U
(b) flexor digitorum sublimis: 7.5 U to 30 U
(c) flexor carpi ulnaris: 10 U to 40 U
(d) flexor carpi radialis: 15 U to 60 U
(e) biceps brachii: 50 U to 200 U.
Each of the five indicated muscles has been injected at the same treatment session, so that the patient receives from 90 U to 360 U of upper limb flexor muscle BOTOX® by intramuscular injection at each treatment session.
To treat migraine, pericranial (symmetrically into glabellar, frontalis and temporalis muscles) injection of BOTOX® has showed significant benefit as a prophylactic treatment compared to vehicle as measured by decreased measures of migraine frequency, maximal severity, associated vomiting and acute medication use over the three month period following the 25 U injection.
Additionally, intramuscular botulinum toxin has been used in the treatment of tremor in patients with Parkinson's disease, although it has been reported that results have not been impressive. Marjama-Jyons, J., et al., Tremor-Predominant Parkinson's Disease, Drugs & Aging 16(4); 273-278:2000.
In addition to having pharmacologic actions at the peripheral location, botulinum toxins may also have inhibitory effects in the central nervous system. Work by Weigand et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1976; 292, 161-165, and Habermann, Naunyn-Schmiedeberg's Arch. Pharmacol. 1974; 281, 47-56 showed that botulinum toxin is able to ascend to the spinal area by retrograde transport.
A Botulinum toxin has also been proposed for the treatment of rhinorrhea, hyperhidrosis and other disorders mediated by the autonomic nervous system (U.S. Pat. No. 5,766,605), tension headache, (U.S. Pat. No. 6,458,365), migraine headache (U.S. Pat. No. 5,714,468), post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), pain treatment by intraspinal toxin administration (U.S. Pat. No. 6,113,915), Parkinson's disease and other diseases with a motor disorder component, by intracranial toxin administration (U.S. Pat. No. 6,306,403), hair growth and hair retention (U.S. Pat. No. 6,299,893), psoriasis and dermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. No. 6,423,319, various cancers (U.S. Pat. No. 6,139,845), pancreatic disorders (U.S. Pat. No. 6,143,306), smooth muscle disorders (U.S. Pat. No. 5,437,291, including injection of a botulinum toxin into the upper and lower esophageal, pyloric and anal sphincters)), prostate disorders (U.S. Pat. No. 6,365,164), inflammation, arthritis and gout (U.S. Pat. No. 6,063,768), juvenile cerebral palsy (U.S. Pat. No. 6,395,277), inner ear disorders (U.S. Pat. No. 6,265,379), thyroid disorders (U.S. Pat. No. 6,358,513), parathyroid disorders (U.S. Pat. No. 6,328,977). Additionally, controlled release toxin implants are known (see e.g. U.S. Pat. Nos. 6,306,423 and 6,312,708).
Adrenergic nerves release norepinephrine as the neurotransmitter for the sympathetic nervous system. The sympathetic system activates and prepares the body for vigorous muscular activity, stress, and emergencies. Adrenergic drugs stimulate the adrenergic nerves directly by mimicking the action of norepinephrine or indirectly by stimulating the release of norepinephrine. An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine (adrenaline). Thus, it is a kind of sympathomimetic agent. Alternatively, it may refer to something which is susceptible to epinephrine, or similar substances, such as a biological receptor (specifically, the adrenergic receptors).
Adrenergic agonists stimulate a response from the adrenergic receptors. The five categories of adrenergic receptors are: α1, α2, β1, β2, and β3, and agonists vary in specificity between these receptors, and may be classified respectively. However, there are also other mechanisms of adrenergic agonism. Epinephrine and norepinephrine are endogenous and broad-spectrum. More selective agonists are more useful in pharmacology.
A great number of drugs are available which can affect adrenergic receptors. Each drug has its own receptor specificity giving it a unique pharmacological effect. Other drugs affect the uptake and storage mechanisms of adrenergic catecholamines, prolonging their action. Agents that work with and activate the adrenergic receptors include alpha- and beta-adrenergic agonists. Agents that increase neurotransmission in endogenous chemicals such as epinephrine and norepinephrine include amphetamines, cocaine, methylenedioxymethamphetamine (MDMA), tyramine, nicotine, caffeine, and methylphenidate. Agents that exhibit aspects of both of these modes include ephedrine and pseudoephedrine.
Adequate treatments for incontinence associated with sexual activity are currently lacking, therefore long-lasting, minimally invasive methods of treatment are desirable.